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Uncertainty and anticipation in anxiety: an integrated neurobiological and psychological perspective
Open accessAbstract
Uncertainty about a possible future threat disrupts our ability to avoid it or to mitigate its negative impact and thus results in anxiety. Here, we focus the broad literature on the neurobiology of anxiety through the lens of uncertainty. We identify five processes that are essential for adaptive anticipatory responses to future threat uncertainty and propose that alterations in the neural instantiation of these processes result in maladaptive responses to uncertainty in pathological anxiety. This framework has the potential to advance the classification, diagnosis and treatment of clinical anxiety.
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“According to Grupe's “uncertainty and anticipation model of anxiety” (UAMA) theory (23), the overestimation of threat costs and probabilities causes exaggerated emotional and behavioral reactivity in anxious individuals”
From Anticipatory threat responses mediate the relationship between mindfulness and anxiety: A cross-sectional study (2022) · cites this paper as [23]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“As noted by Grupe and Nitschke (2013), limited habituation in mPFC biases information processing towards negative/threatening frameworks; individuals for whom this system is working more typically may be less susceptible to anxiety even if they are diagnosed with ASD.”
From Sensory, emotional and cognitive contributions to anxiety in autism spectrum disorders (2017) · cites this paper as Grupe and Nitschke, 2013
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Disruptions to this network may then lead to “more vivid or visceral simulations of potential events” (p. 492) and heighten a bias towards threat especially in uncertain situations.”
From Sensory, emotional and cognitive contributions to anxiety in autism spectrum disorders (2017) · cites this paper as Grupe and Nitschke, 2013
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“A seminal article on the neurobiology of IU (Grupe and Nitschke, 2013) suggests that medial orbitofrontal cortex and insula provide information about the subjective value of potential events, balancing an individual’s feelings of probable risk separate from a reasoned consideration of risk.”
From Sensory, emotional and cognitive contributions to anxiety in autism spectrum disorders (2017) · cites this paper as Grupe and Nitschke, 2013
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Both crises bring uncertainty, loss, and change, and induce grief, anxiety, and distress.8”
From Psychological responses, mental health, and sense of agency for the dual challenges of climate change and the COVID-19 pandemic in young people in the UK: an online survey study (2022) · cites this paper as [8]
Experimental — accuracy not yet measured
The cited source says what the claim attributes to it.
In the citing paper
“Although people differ in their tolerance of uncertainty and ambiguity, many find uncertainty disquieting or avoid it altogether in situations that are personally threatening 66 .”
From Predictors and consequences of intellectual humility (2022) · cites this paper as [66]
The cited source says what the claim attributes to it.
In the citing paper
“The amygdala, a key region for threat processing, shows heightened activation to uncertain or ambiguous cues in anxious individuals (64).”
From Predictive coding and neurocomputational psychiatry: a mechanistic framework for understanding mental disorders (2026) · cites this paper as [64]
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In the citing paper
“Recent perspectives consider anxiety to be a future-oriented emotional state”
From Anticipatory threat responses mediate the relationship between mindfulness and anxiety: A cross-sectional study (2022) · cites this paper as [23]
The cited source says what the claim attributes to it.
In the citing paper
“Recent studies suggest that abnormal and excessive anticipatory responses to unpredictable threats play an important role in anxiety symptoms”
From Anticipatory threat responses mediate the relationship between mindfulness and anxiety: A cross-sectional study (2022) · cites this paper as [23]
The cited source says what the claim attributes to it.
In the citing paper
“Excessive reactivity to uncertainty plays a central role in anxiety”
From Responding to uncertain threat: A potential mediator for the effect of mindfulness on anxiety (2021) · cites this paper as Grupe & Nitschke, 2013
The cited source says what the claim attributes to it.
In the citing paper
“it has been argued that extreme responses to uncertainty play a critical role in pathological anxiety (Grupe & Nitschke, 2013).”
From Responding to uncertain threat: A potential mediator for the effect of mindfulness on anxiety (2021) · cites this paper as Grupe & Nitschke, 2013
The cited source says what the claim attributes to it.
In the citing paper
“Individuals often believe these cognitions and behaviors are productive, thus sustaining cycles of use [15].”
The cited source says what the claim attributes to it.
In the citing paper
“Humans display sustained vigilance and defensive responses under conditions of uncertainty [31,32,85].”
From Impact of Media-Induced Uncertainty on Mental Health: Narrative-Based Perspective. (2025) · cites this paper as [31]
The cited source says what the claim attributes to it.
In the citing paper
“Hypervigilance has been singled out as 1 of 5 key processes involved in aberrant and excessive anticipatory responding to uncertainty [31].”
From Impact of Media-Induced Uncertainty on Mental Health: Narrative-Based Perspective. (2025) · cites this paper as [31]
The cited source says what the claim attributes to it.
In the citing paper
“Psychological and neural mechanisms through which uncertainty-inducing stressors elicit negative mental states, particularly anxiety, and may lead to psychopathology have been extensively described in the literature [31,35,36,57,119,120], and these models are broadly relevant in the present context.”
From Impact of Media-Induced Uncertainty on Mental Health: Narrative-Based Perspective. (2025) · cites this paper as [31]
In the citing paper
“Within this line of work, uncertainty has emerged as an important moderator of this observed individual difference in sensitivity to threat cues, with individuals with anxiety disorders demonstrating enhanced reactivity to uncertain compared to certain threat cues (Bradford, Kaye, & Curtin, 2014a; Bradford, Magruder, Korhumel, & Curtin, 2014b; Grupe & Nitschke, 2013).”
From Cued for Risk: Evidence for an Incentive Sensitization Framework to Explain the Interplay between Stress and Anxiety, Substance Abuse, and Reward Uncertainty in Disordered Gambling Behavior (2019) · cites this paper as Grupe & Nitschke, 2013
In the citing paper
“When safety is in doubt, subcortical inhibition by the vmPFC is decreased and amygdala activity is enhanced (Grupe and Nitschke, 2013).”
From Exposed to events that never happen: generalized unsafety, the default stress response, and prolonged autonomic activity (2017) · cites this paper as Grupe and Nitschke, 2013
In the citing paper
“There is increasing evidence that NPS are caused by dysfunction in specific networks (Dichter et al., 2014; Greicius, 2008; Grupe and Nitschke, 2013; Hamon and Blier, 2013; Menon, 2011; Price and Drevets, 2010; Price and Drevets, 2012; Tromp et al., 2012; Uhlhaas, 2013), with overlap between proposed networks and conditions.”
From Neuropsychiatric symptoms in Alzheimer's disease: what might be associated brain circuits? (2015) · cites this paper as Grupe and Nitschke, 2013
In the citing paper
“In Grupe et al.’s schematic, this overlaps with circuits that subsume behavioral and cognitive avoidance (Grupe and Nitschke, 2013).”
From Neuropsychiatric symptoms in Alzheimer's disease: what might be associated brain circuits? (2015) · cites this paper as Grupe and Nitschke, 2013
In the citing paper
“Our review of the data on the biology of NPS in AD suggests specific circuit alterations underlying the link of AD pathology with NPS, with these associations being particularly compelling for agitation and apathy in specific circuits (Fig. 1 and Fig. 2) given intriguing overlap with relevant brain circuits (Grupe and Nitschke, 2013).”
From Neuropsychiatric symptoms in Alzheimer's disease: what might be associated brain circuits? (2015) · cites this paper as Grupe and Nitschke, 2013
In the citing paper
“Thus, agitation in AD involves miscalculation of the magnitude of potential threats, accompanied by increased threat attention and vigilance, and/or heightened reactivity to threat uncertainty (Grupe and Nitschke, 2013) (see their fig. 1a, 1b, and 1f).”
From Neuropsychiatric symptoms in Alzheimer's disease: what might be associated brain circuits? (2015) · cites this paper as Grupe and Nitschke, 2013
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Research works printed but not linked: 2
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 4th edn (American Psychiatric Press, 2000).
- Beck, A. T. & Emery, G. Anxiety Dsorders and Phobias: a Cognitive Perspective (Basic Books, 1985).
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Sorted by citations
Neuronal circuits for fear and anxiety
Tovote, P., Fadok, J. P., & Lüthi, A. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3945 · Cited by 1,786
Into the unknown: A review and synthesis of contemporary models involving uncertainty
Carleton, R. N. (2016) · Journal of Anxiety Disorders · doi:10.1016/j.janxdis.2016.02.007 · Cited by 1,104
Using Neuroscience to Help Understand Fear and Anxiety: A Two-System Framework
LeDoux, J. E., & Pine, D. S. (2016) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2016.16030353 · Cited by 1,035
Enck, P., Aziz, Q., Barbara, G., Farmer, A. D., Fukudo, S., Mayer, E. A., Niesler, B., Quigley, E. M. M., Rajilić-Stojanović, M. D., Schemann, M., et al. (2016) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2016.14 · Cited by 1,102
Anxiety and the Ecological Crisis: An Analysis of Eco-Anxiety and Climate Anxiety
Pihkala, P. (2020) · Sustainability · doi:10.3390/su12197836 · Cited by 978
Metadata
- Authors
- Grupe, D. W., & Nitschke, J. B.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Nitschke, Jack B.
- Venue
- Nature Reviews Neuroscience
- Published
- 2013-06-20
- Volume
- 14
- Issue
- 7
- Pages
- 488-501
- ISSN
- 1471-003X (ISSN-L)
- 1471-0048
- PMC
- PMC4276319
- OpenAlex
- W2004873925
- Semantic Scholar
- 76c65983fa7dc2ad5afb5128da8f60ef082964b2
- Cited by
- 2,007
- References
- 223
- Citations by year
- 2026: 243 · 2025: 207 · 2024: 199 · 2023: 174 · 2022: 232 · 2021: 255 · 2020: 159 · 2019: 127 · 2018: 101 · 2017: 106 · 2016: 107 · 2015: 56 · 2014: 37 · 2013: 3
- FWCI
- 11.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature reviews. Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5k02mh082130-05)
- National Institute of Mental Health (K02‑MH082130, R01MH074847, R01-MH74847)
- Topics
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Keywords
- anxiety, uncertainty, anticipation, threat anticipation, neurobiology of anxiety, anticipatory responses, anxiety treatment
- MeSH terms
- Adaptation, Psychological, Anxiety, Attention, Brain, Decision Making, Humans, Neurobiology, Uncertainty
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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